Lactose‐Derived Carbohydrates Induce Sexually Dimorphic Nutritional Programming Effects on Lifespan in <i>Drosophila melanogaster</i>

Early-life nutrition can exert long-lasting effects on later-life health. Given that lactose is extensively consumed during early mammalian development, this raises the intriguing possibility that lactose or its constituent galactose may exert beneficial nutritional programming effects. We tested here whether early-life (larval period) co-consumption of galactose and glucose (GALGLU; as in hydrolysed lactose) shapes later-life (adult) lifespan in Drosophila melanogaster. Larval GALGLU versus isocaloric glucose consumption (GLU) significantly extended the developmental time of larvae, increased the pupal volume, decreased pupal oxygen consumption, and reduced the pupal mitochondrial mass. These early-life effects were translated into sexually dimorphic effects on adult lifespan. Specifically, larval GALGLU consumption extended the lifespan of females when challenged with an obesogenic adult diet, whereas it reduced lifespan in males. To identify molecular correlates of the female-specific benefit, we profiled transcriptomes and lipidomes. Notably, larval GALGLU induced later-life transcriptional activation of cuticular hydrocarbon (CHC)-synthesizing enzymes, including the diene-producing desaturase Fad2, without changes in the monounsaturated fatty acid (MUFA)-producing desaturase Desat1, indicating increased MUFA demand without increased supply. Lipidomic analysis revealed decreased MUFA-containing and increased polyunsaturated fatty acid (PUFA)-containing glycerophospholipids. These data suggest that enhanced CHC biosynthesis depletes cellular MUFAs, driving compensatory incorporation of PUFAs into glycerophospholipids. Concluding, early-life galactose and glucose co-consumption programs sexually dimorphic lifespan, specifically by counteracting the lifespan-shortening effects of obesogenic diets in adult females, and redirects adult female lipid metabolism toward a PUFA-enriched glycerophospholipid profile.